Flesinoxan challenge suggests that chronic treatment with paroxetine in rats does not desensitize receptors controlling 5-HT synthesis |
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| Affiliation: | 1. Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy;2. Laboratory of Personalized and Preventive Medicine, University of Brescia, 25123 Brescia, Italy;3. Unit of Biology and Genetic, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy;1. INSERM, Research Unit 1000 “Neuroimaging and Psychiatry”, Paris Saclay University, Paris Descartes University, DIGITEO Labs, Gif sur Yvette, France;2. EPS Barthelemy Durand, Etampes, France;3. IMIV, U1023 Inserm/CEA/Université Paris-Sud and ERL 9218 CNRS, Université Paris-Saclay, CEA/SHFJ, Orsay, France;4. AP-HP, Psychiatry Department, Tarnier Hospital, Groupe Hospitalier: Hôpitaux Universitaires Paris Centre, Paris, France;5. INSERM U1130 Research Unit, CNRS UMR 8246, UPMC UM CR18, Paris, France;6. Groupe Hospitalier Nord Essonne, Psychiatry Department 91G16, Orsay, France |
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| Abstract: | It has been proposed that the desensitization of 5-HT1A (5-hydroxytryptamine; serotonin) receptors following chronic therapy with selective serotonin reuptake inhibitors (SSRIs) is necessary for their therapeutic efficacy. Stimulation of the 5-HT1A receptors decreases serotonin (5-HT) synthesis and release, but it is not clear if the receptors are fully desensitized following chronic SSRI treatment. The main objective of this study was evaluation of ability of 5-HT1A receptors to modulate 5-HT synthesis after 14-day paroxetine treatment. 5-HT1A receptor sensitivity following chronic administration of the SSRI paroxetine was assessed by the ability of an acute challenge with the 5-HT1A agonist, flesinoxan, to modulate 5-HT synthesis in the rat brain. The rates of 5-HT synthesis were measured using the α-[14C]methyl-l-tryptophan autoradiographic method. The rats were treated for 2 weeks with paroxetine (10 mg/(kg day), s.c., delivered by osmotic minipump). After this treatment, the rats received an acute challenge with flesinoxan (5 mg/kg, i.p.), while the control rats were injected with the vehicle. Forty minutes following the flesinoxan injection, the tracer, α-[14C]methyl-l-tryptophan, was injected over 2 min. 5-HT synthesis rates were calculated from autoradiographically measured tissue tracer concentrations and plasma time–activity curves. The results demonstrated that the acute flesinoxan challenge produced a significant decrease in 5-HT synthesis rates throughout the rat brain. The greatest decrease was observed in the ventral hippocampus, somatosensory cortex and the ascending serotonergic cell bodies. In comparison with data reported on an acute challenge with flesinoxan in naïve rats (rats without any other treatment), the results presented here suggest a greater effect of flesinoxan on synthesis reduction in rats chronically treated with paroxetine. The results also suggest that the 5-HT receptors were not fully desensitized by paroxetine treatment, and that the stimulation of 5-HT1A receptors with an agonist is still capable of reducing 5-HT synthesis. |
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